Blood Components Separation
Separation of blood into a plasma fraction and a cellular component fraction is desirable for many medical reasons. For example, separation of blood into plasma fractions and cellular component fractions provides for a collection of plasma alone, with the cellular component being returned to the donor with an optionally suitable portion of replacement fluid. Thus, continuous plasmapheresis provides for the collection of plasma from donors without the removal of the cellular components of the blood. Plasma donation from a patient or donor is generally allowed about twice a week whereas the whole blood donation is allowed once in every two months. Secondly, continuous plasmapheresis can be used therapeutically to remove pathologic substances contained in the plasma portion of the blood, as disclosed by Popovich et al. in U.S. Pat. No. 4,191,182. This can be accomplished by separating the cellular components from the diseased plasma and returning the cellular components to the patient in admixture with a suitable replacement fluid, or by further fractionating the patient's plasma to remove the unwanted substances and returning a major portion of the patient's plasma with the cellular components.
The separation of blood into cellular component fractions and plasma fractions has inherently some difficulties and complications. A brief discussion of the makeup of blood is shown herein for illustration purposes. Approximately 45% of the volume of blood is in the form of cellular components. These cellular components include red cells, white cells and platelets. If cellular components are not handled correctly, the cells may lose their functionality and become useless. Plasma makes up the remaining 55% of the volume of blood. Basically, plasma is the fluid portion of the blood which suspends the cells and comprises a solution of approximately 90% water, 7% protein and 3% of various other organic and inorganic solutes. As used herein, the term “plasmapheresis” refers to the separation of a portion of the plasma fraction of the blood from the cellular components thereof.
Ultrafiltration has been widely used on a batch-type or continuous basis as a substitute for, or in combination with, dialysis methods in artificial kidneys and the like. In any plasmapheresis-type process effected by ultrafiltration there are various problems which occur during the fractionating of the blood by passing it in a parallel flow pattern over a membrane surface, with a transmembrane pressure sufficient to push the plasma portion of the blood therethrough, while allowing the cellular component portion of the blood to remain thereon. One of these problems is that the flow rates must be controlled fairly closely. Thus, if the flow rate employed is too fast at any moment or at any specific region, detrimental turbulence may occur and excess shear force may cause unwanted hemolysis resulting in general destruction of cellular components. On the other hand, if the flow rate and the transmembrane pressure are not controlled adequately the cellular and macromolecular components of the blood will tend to clog up the membrane thus significantly slowing the ultrafiltration rate. Such clogging can also cause hemolysis to occur.
Along the blood flow route in a plasmapheresis apparatus, plasma continues to pass through the filter membrane while cellular component remains in the blood stream. At the downstream region of the separation process, the blood becomes more viscous and the separation efficiency decreases drastically. This fouling effect or “concentration polarization” phenomenon becomes obvious in a conventional batch-wise or continuous ultrafiltration process. For example, U.S. Pat. No. 3,705,100 to Blatt et al., issued on Dec. 5, 1972, discloses a process and apparatus for a blood fractionating process on a batch basis. Furthermore, U.S. Pat. No. 4,191,182 to Popovich et al., issued Mar. 4, 1980, discloses means for continuous plasmapheresis including blood input pumping means and plasma outflow pumping means. Though the average flow rate of the disclosed device is within the non-hemolysis range, the local flow rate and its shear force at any moment and/or at any specific region of the filter membrane may not be adequate to effect the most efficient plasmapheresis. Concentration polarization usually occurs at a later stage in a batch plasmapheresis or at a downstream region in a continuous plasmapheresis.
To alleviate the concentration polarization drawbacks, Solomon et al. in U.S. Pat. No. 4,212,742 discloses a filtration device employing a microporous filtration membrane. The filtration flow channels along the surface of the upstream side of the membrane wall are provided with gradually and uniformly increases from the inlet end to the outlet end of the flow channel, whereby the membrane wall shear force of the suspension in laminar flow through the flow channel gradually and uniformly varies along the length of the flow channel from a maximum value at its inlet end to a minimum value at its outlet end. There are complex issues in designing and operating such a unit. Further, Solomon et al. device requires enormous membrane surfaces for blood plasma separation which appear not economically practical.
For the purposes of increasing the transmembrane pressure drop hopefully to catch a higher separation efficiency and a less concentration polarization effect, Fischel in U.S. Pat. No. 5,034,135, Schoendorfer in U.S. Pat. No. 5,194,145, Duff in U.S. Pat. No. 5,234,608, Fischel in U.S. Pat. No. 5,376,263, and Brown in U.S. Pat. No. 5,529,691 all disclose a blood separating system comprising high rotational velocity flow applying centrifugal forces aiming for added transmembrane pressure drop. During high centrifugal rotation, a portion of the cellular components may undesirably remain in the rotational device or inside pores of the filter membrane for a prolonged time and may subject to hemolysis, cellular damage or membrane clogging. For centrifugal-type separation processes, the local shear force for the cellular components of the blood concentrate fraction is the highest at about the outermost periphery of the separation apparatus, such as a spinner-type device and the like. The requirement of a proper shear force at the outermost region in a rotational separator apparently limits the size, and therefore the capacity, of the separation apparatus or the spinner. The centrifuge-type separation apparatus also generally suffers concentration polarization disadvantages.
Alternately, to create adequate local flow rate and subsequently local shear force in a plasmapheresis process, Duggins in U.S. Pat. No. 4,735,726 discloses a process for continuous plasmapheresis comprising conducting blood over a microporous membrane in a reciprocatory pulsatile flow pattern. The pulsatile flow is known to cause certain degrees of turbulence as the pulsatile flow rate changes constantly which may possibly cause cell damage and membrane clogging. Duggins discloses a damage-controlling method to compensate for the shortcomings of the pulsatile flow in a continuous plasmapheresis by reducing the transmembrane pressure difference to below zero during each forward and reverse flow. This additional equipment setup and control mechanism for repetitively reversing the transmembrane pressure difference makes this process less economically attractive.
Virus Infection
AIDS (acquired immuno-deficiency syndrome) is one of the leading causes of death for Americans between the ages of 25 and 44. HIV (human immunodeficiency virus) is the virus most researchers believe causes AIDS. The virus exists in the blood circulation of a patient in two forms. One form is as cell-free virus or mature virion having a lipid envelope, and the other is as cell-associated virus or replicating virus in the infected cells. According to the Center for Disease Control (CDC), the definition of AIDS includes two factors: HIV positive and CD4 (T-cell) count below 200 or presence of one or more opportunistic infections. About 47 million people worldwide have been infected with HIV since the start of the epidemic.
The virus attacks the immune system and leaves the body vulnerable to a variety of life-threatening illnesses and cancers. Common bacteria, yeast, parasites, and viruses that ordinarily do not cause serious disease in people with fully functional immune systems can cause fatal illnesses in people with AIDS. According to the teachings in U.S. Pat. No. 5,419,759, the full-blown AIDS is characterized by weight loss, fever, severe headache, neck stiffness, arthralgia, and skin rash. The virus is essentially an intracellular parasite and in order to survive and perpetuate itself it has to penetrate and infect the host cells. The lipid envelope with its glycoprotein spikes provides the means for penetrating and infecting the white cells. The virus replicates inside the infected cells and produces mature virions with lipid envelope and glycoprotein spikes, budding from the membrane of the infected cell. These mature virions in turn penetrate and infect the new and healthy cells as they are released from the hematopoietic system, and the vicious cycle goes on.
T-cells (or T-lymphocytes) are white blood cells that play important roles in the immune system. There are two main types of T-cells. One type has molecules called CD4 on its surface. These “helper” cells orchestrate the body's response to certain microorganisms such as viruses. The other T-cells, which have a molecule called CD8, destroy cells that are infected and produce antiviral substances. The target host cells invaded by HIV known today include CD4 T-lymphocytes, monocytes, macrophages and colorectal cells.
HIV is able to attach itself to the CD4 molecule, allowing the virus to enter and infect these cells. Even while a person with HIV feels well and has no symptoms, billions of CD4 T-cells are infected by HIV and are destroyed each day and billions more CD4 T-cells are produced to replace them.
Other sexually transmitted diseases may include human papilloma virus and hepatitis B virus, which are associated with cervical carcinoma and hepatocellular carcinoma, respectively.
Separation of Virus-Infected Blood Components
Naficy in U.S. Pat. No. 5,419,759 and U.S. Pat. No. 5,484,396, the entire contents of both being incorporated herein by reference, discloses that the HIV is an enveloped virus having lipids in its outer envelope. Naficy also discloses using diethyl ether to dissolve or destroy the lipid envelope of HIV, thereby destroying the glycoprotein spikes and rendering the virus unable to penetrate and infect the healthy cells. Earlier, Cham in U.S. Pat. No. 4,895,558, entire contents of which are incroporated herein by reference, discloses a method for autologous plasma delipidation of an animal using a continuous flow system with means to delipidate the plasma using a lipid solvent, wherein the preferred solvent is di-isopropyl ether.
Cham in U.S. Pat. No. RE37,584, entire contents of which are incorporated herein by reference, discloses a solvent extraction method for de-virusing plasma, wherein the suitable solvents may comprise mixtures of hydrocarbons, ethers and alcohols. Though it is known in the prior art that alcohol, ether, hydrocarbons, or combination thereof is feasible in de-virusing the plasma, none of the above-cited prior art discloses a separation apparatus and methods under an orbital motion that has optimal local shear forces and desired quality flow output for the intended HIV delipidation therapy.
Hildreth in U.S. patent application Publication No. 2002/0128227 and Publication 2002/0132791, entire contents of which are incorporated herein by reference, discloses: methods of reducing the risk of transmission of a sexually transmitted pathogen by contacting the pathogen or cells susceptible to infection by the pathogen with a beta-cyclodextrin; methods for reducing the risk of transmission of a sexually transmitted pathogen to or from a subject by contacting the pathogen or cells susceptible to the pathogen in the subject with a pharmaceutical composition containing a beta-cyclodextrin.
To reduce the risk of transmission of a sexually transmitted pathogen to or from a subject is important. However, to treat the subject already infected with a sexually transmitted pathogen becomes equally or even more important. Hildreth fails to disclose a method or system for treating a patient infected with the sexually transmitted pathogen or cells susceptible to the pathogen to extend the patient's quality of life.
McBurney et al. in U.S. Pat. No. 6,548,241 and U.S. patent application Publication No. 2003/0186213, the entire contents of both being incorporated herein by reference, disclose a platelet/additive solution comprising bicarbonate, citrate, glucose and a photosensitizer for inactivating pathogens. One embodiment is to place the solution with a photosensitizer, preferably 7,8-dimethyl-10-ribityl-isalloxazine, in a photopermeable container such as a blood bag and agitated while exposing to photoradiation.
Therefore, there is an unmet clinical need to provide an effective and economical plasmapheresis and de-virus processes in an extracorporeal pathogen reduction system by minimizing the cellular damage while increasing the quality flow output for reinfusion purposes. This may be achievable by controlling the local flow rate and local shear force of an apparatus system comprising an orbital motion to minimize or eliminate problems of undesired turbulence, concentration polarization, or incomplete liquid-liquid mixing encountered in a conventional separation apparatus setup.